Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536) describe hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. However, for certain applications wherein elongational extension of the adhesive is required due to distension of the tissue (e.g., in an intestinal anastomosis), hydrogel tissue adhesives with greater elongation-to-break are needed. The elongation-to-break of the adhesives described by Kodokian et al. can be improved by reducing the crosslink density of the hydrogel by adjusting the concentration of the reactants such that one reactant is in excess or by using a reactant having the same functionality, but a higher molecular weight. However, because it is the crosslinks that resist hydrogel swelling and confer strength to the hydrogel network, a lower crosslink density often results in a greater equilibrium water content, which leads to extreme swelling and rapid loss of mechanical properties in an aqueous environment.
Engbers (U.S. Pat. No. 6,150,472) describes multi-functional site-containing block copolymers and their use to make hydrogels. These multi-functional site-containing block copolymers are made by coupling oligomers or polymers having many reactive groups, such as poly(ethylene imine), to the ends of a linear polymer. The use of these multi-functional site-containing block copolymers provides hydrogels with improved properties relative to the linear 2-functional site polymers with which they are compared. However, the large multiplicity of reactive groups doesn't provide optimum control of crosslinking. Additionally, the hydrogel properties of a block copolymer with a relatively short linear central component is dominated by the multi-functional site polymers on the ends, with the linear portion having little effect on the elongational strength. Furthermore, the presence of a large number of unreacted functional groups, such as amines in a poly(ethylene imine)-ended polymer, contributes to an undesirably high degree of pH sensitivity, water swelling, and loss of modulus of the hydrogel in an aqueous environment.
Grinstaff et al. (U.S. Patent Application Publication No. 2004/0086479) describe dendritic polymers and crosslinked gels made therefrom. The dendritic polymers have reactive groups at the ends of their branches that are capable of crosslinking with other polymers. The dendritic polymers have characteristics that are similar to those of the multi-functional site-containing block copolymers described by Engbers above, in that they also have a large multiplicity of reactive groups on the chain ends.
Therefore, the problem to be solved is to provide a tissue adhesive material with a suitable balance of mechanical properties, specifically, elongation to break, tensile strength, and water swell, for use in surgical procedures as well as other medical applications.
Applicants have addressed the stated problem by discovering branched end reactants comprising a linear or branched polymer having two or three functional groups at each of the ends of the polymer chain or at the end of the polymer arms. The branched end reactants are used to prepare crosslinked hydrogel adhesives having a good balance of mechanical properties in an aqueous environment.